Calcium Homeostasis and Bones

Question 1

Where is the majority of body calcium stored, and where is the rest of it stored

Answer 1

99% is stored in skeleton as hydroxyapatite.

Around 1% is stored intracellularly = But remember that it is not free, but sequestered in organaelles like endoplasmic reiculum and skeletal muscle.

Extracellular Ca is only 0.1% and this is what we measure. 45% of this is in the free ionised form, while remaining 55% is bound. Can be bound to all sorts of things, but majority is to albumin. Therefore alterations in albumin can change Ca levels, so needs to be albumin adjusted.

Question 2

How does acid base balance effect calcium levels

Answer 2

If you become acidotic = H+ competes with Ca ions for binding to plasma proteins. So acidosis increases the amount of free Ca in the blood, without actually changing the total amount of Ca you have

So this makes them look hypercalcaemic, when actually it is normal.

Question 3

How much calcium do we normally need?

Normal adults, and lactating women

Answer 3

Normally we should have 1000mg/day for adults. Lactating women need 1250.

Question 4

Specifically hwo is Ca absorbed through the gut lining?

Answer 4

Ca absorbed through TRPV6 Ca channel in the microwilli. Then it is boudn to Ca proteins calmodulin and calbindin. Then moves through cell through baso-lateral membrane and into extracell fluidby exocytosis or through the Ca/ATPase transporter.

Question 5

How is calcium excreted in detail

Answer 5

All of the free ionised calcium in blood, and the small amount bound to anions is filtered out by glomeruli, but 99% of it is reabsorbed.
80% of this is passive reabsorbtion, but 20% is done by the TRPV5 receptor (Ca epithelial receptor)

Question 6

Which 2 hormones increase Ca levels

Answer 6

PTH and Vit D

Question 7

Which main hormone reduces Ca levels

Answer 7

Calcitonin

Question 8

What are the main; receptor type, action, and effects of PTH

Answer 8

Receptor: Binds to a GCPR known as PTHR1

Signal for synthesis = Low Ca causes production from chief cells in parathyroid glands

Actions:

1) Increased bone resorption
2) Increased phosphate secretion in kidneys
3) Reduced calcium excretion in the kidneys
4) Increased vit D activation in the kidneys

Net effect = Increased Ca, reduced Phosphate

Question 9

What are the main; receptor type, action, and effects of Vitamin D/Calcitriol

Answer 9

Receptor: Binds to a nuclear receptor

Signal for synthesis = Low calcium, low phosphate, or PTH (this causes more activation of vit D).

Actions:

1) Increased bone formation and mineralisation
2) Increased bone remodelling
3) Increased Ca absorption in the gut
4) Increased Ca and Phosphate resorption in the kidneys

Net effect = Increases both Ca and phospahate

Question 10

What are the main; receptor type, signal for synthesis, action, and net effects of Calcitonin

Answer 10

Receptor: Binds to a GCPR

Signal for synthesis = High Ca levels causes production of calcitonin from the C cells in the parathyroid

Actions:

1) Reduced Ca reabsorption in the kidneys
2) Increased phosphate excretion in the kidneys
3) Inhibits osteoclast function in bone (so less breakdown and liberation of Ca)

Net effect = Reduces calcium

Question 11

Cause and blood test changes in primary hyperparathyroidism

Answer 11

Cause = Usually defect in para gland like benign tumour

Bloods = Increased PTH, increased Ca, increased Vit D, reduced phosphate levels.

Question 12

What happens in secondary hyperparathyroidism? Specifically in the reanal osteodystrophy case?

Answer 12

So secondary hyperparathyroidism occurs because of a defect in feedback control, which is often due to CKD

In renal osteodystrophy = The kidneys are no longer able to respond normally to PTH. So PTH’s effects of increased Ca resorption and causing more Vit D activation do not occur. This means only place PTH can act to increase Ca levels is by increasing bone resorption = Causing osteomalacia

Bloods = In this case again PTH is high, but it is high despite a LOW calcium.

Question 13

What is the name of the receptor that senses calcium levels

Answer 13

CaSR or Ca sensing receptor = Is sensitive to serum Ca concentrations.

There are now synthetic allosteric activators of CaSR = Called calcimimetics that are used for the treatment of hyperparathyroidism

Question 14

What is the name and process of the disorder that is due to a mutation in CaSR

Answer 14

Familial hypocalciuric hypercalcaemia = In neonates you get severe hyperparathyroidism.
You can also get an autosomal dominant hypoparathyroidism which is because of an activating mutation of CaSR.

Urine = Increased action of PTH therefore means more reabsorption of Ca in kidneys so hypocalciuric occurs.

Question 15

What is PTHrP, where does it come from and what does it cause

Answer 15

PTH related peptide can also bind to the PTHR1 receptor and act just like PTH

Cancer = Can be produced commonly by cancer cells so causes the hypercalcaemia seen in malignancy.

Question 16

What is the biologically active form of Vit D

Answer 16

1a,25-dihydroxyvitamin D3 (calcitriol) = 1a hydroxylation is done in the kidney

Question 17

Which type of Vitmain D do we usually measure in the blood

Answer 17

25-hydroxyvitamin D = This is calcidiol which is considered a good surrogate marker of Vit D status. This is because it is actually a metabolite of Vit D.

Question 18

What is the Vit D synthesis pathway

Answer 18

Starts in keratinocytes = Needs UV light to convert 7-dehydrocholesterol into Vitamin D3 (cholecalciferol)

Then this Vit D needs to be activated = This Vit D3 or Vit D2 (dietary vitamin D) is hydroxylated first in the liver at the 25 position.
Then at the 1 position in the kidneys

Question 19

What effects kidney 1a hydroxylation of vit D

Answer 19

Unlike 25 liver hydroxylation, the 1 hydroxylation in the kidneys is tightly regulated and increased by higher PTH levels, low Ca level, Low phosphate levels.

Question 20

Where are the inactive metabolites of Vit D stored, and what are these

Answer 20

Vit D2 = (dietary vit D we get from diet),
Vit D3 = We get from UV light converting 7-dehydrocholesterol into this in the skin
Calcidiol = 25-hydroxyvitamin D

These are all stored in body fat and can be released when needed. Which allows for storage of excess Vit D made in the summer.

Question 21

What is the name of the transmembrane transporter for VIt D

Answer 21

Megalin = Can transport calcidiol and calcitriol

Question 22

How does Vitamin D binding to its receptor work to cause an effect

Answer 22

Remember Vit D is lipophilic so it acts via a nuclear receptor. Both calcidiol and calcitriol can enter cell, then calcidiol can be hydrogylated to calcitriol in the mitochondria

Calcitriol = Can then bind to VDR vitamin D receptor. VDR has a heterodimer partner = Retinoid X receptor, and together they bind specific Vitamin D response elements on certain DNA sequences.
Here they make transcriptional changes

Question 23

What is the name of the condition caused by Vit D def in children, and which is the issues it causes

Answer 23

Rickets

Failure for the endochrondral bone to mineralise in the growth plate, and delayed calcification.
Then weight bearing causes deformity in the limbs
Common deformities = Craniotabes, delayed closure of anterior fontanelle, Harrison sulcus, thickening of ankles.

Question 24

What is the name of the condition caused by Vit D def in Adults, and which is the issues it causes

Answer 24

Osteomalacia = Failure to mineralise newly formed osteoid. Bones look thin on X ray.

Question 25

What is the name of the hormone that controls phosphate levels, and reduces them, and how does it work

Answer 25

Fibroblast growth factor 23

Made in mineralised tissues like osteocytes in response to vitamin D = It causes reduces the expression of NPT2 in the kidneys meaning more phosphate is excreted in the urine.

It is therefore an important mechanism to prevent Vit D mediated hyperphosphataemia

Question 26

How are maternal and foetal Ca balance different in prengnacy

Answer 26

Both pregnancy and lactation are periods of increased Ca requirement.
Foetus is comparitively more hypercalcaemic then mother. WIth Ca ratios of 1.4 to 1

Question 27

How is Ca and Phosphate transported from mother to foetus

Answer 27

Foetal Ca levels are higher, so Ca and phosphate are transported against the conc gradient using Ca transporters.

Question 28

What is the role of Foetal PTHrP

Answer 28

Produced by the foetus which can help regulate placental Ca transportation = DOes this by modifying placental calbindin and the Ca ATPase pump.

Question 29

When does the foetus produce PTH, and what are the levels of PTH and calcitonin like at birth

Answer 29

Can produce PTH by week 12 (PTH does not cross the placenta)

But at birth = PTH levels remain low, with high calcitonin levels.

Question 30

How are maternal levels of PTH, calcitonin, and Vit D different in pregnancy

Answer 30

These change to try and store up as much Ca as possible prior to the foetus requiring lots of Ca.

1) Decreased or normal levels of PTH (so bone stores build up)
2) Increased calcitonin (so bone stores build up_
3) Increased Vit D

Question 31

Should we be giving Vit D supplementation in pregnancy? What effects could Vit D def have in pregnanct?

Answer 31

Yes everyone should get it, particularly asian women.

There is a clear link between developing both T1 and T2 DM with low Cit D. Also studies to show it is important for fertility in mother, and foetal development.

Question 32

How does oestrogen effect bone modelling

Answer 32

1) Inhibits osteoclast function as well as genesis of new osteoclasts.

Question 33

Tell me about RANKL

Answer 33

RANKL (or RANK ligand) = Produced by osteoblasts and binds to RANK receptors on osteoclasts.

Function = Increases osteoclast formation, function and survival

Question 34

WHat is osteoprotegrin

Answer 34

This is also (like RANKL) produced by osteoblasts, and acts as a decoy receptor for RANKL. THerefore prevents excess RANKL binding to osteoclasts.

Question 35

How does denosumab work

Answer 35

A mAb that mimics osteoprotegrin. Therefore prevents RANKL binding to RANK on osteoclasts. Therefore reduces osteoclast function

Question 36

What is sclerostin

Answer 36

Produced by ostecytes and inhibit bone formation

Question 37

What happens if you get osteoporosis during pregnancy

Answer 37

Pregnancy and lactation are both very calcium dependant. YOu need lots.
So you can present with similar things in pregnancy = Loss of height, pain, vertebral fractures.

Important to assess whether this osteoporosis can be attributed to the pregnancy, or it is something underlying.

Pregnancy induced osteoporosis and lactation induced, are both likely to resolve about 6 months after the birth. And both dont increase lifetime risk of osteoporosis